Renal Disease And PK/PD - UCLA CTSI

Renal Disease and PK/PDAnjay Rastogi MD PhDDivision of Nephrology

Drugs and KidneysKidney is one of the major organ of drugelimination from the human bodyRenal disease and dialysis alters thepharmacokinetics and pharmacodynamics ofmost commonly used drugsPolypharmacy is common in renal diseasepatients with a median of 8 drugs being usedPatients with renal disease on an average sufferfrom adverse effects as compared to the generalpopulation

Renal Disease and DrugsDecreased eliminationUremic effectsNephrotoxicity

Estimation of renal functionEffect of renal disease on PK and PDDrug NephrotoxicityManagement of poisoning

NephronReabsorptionFiltrationKidney regulates:- Water- Acid-base balance- Electrolytes- Nitrogenous wasteexcretionSecretion

GFR as an Indicator of KidneyFunctionGFR is an important indicator of CKDReduced GFR in patients with renal diseaseresults from irreversible loss of nephrons1,2– Greater burden is placed on remaining nephrons– Hyperfiltration predisposes to further nephrondestruction50% of nephrons can be lost without functionalimpairment1Patients may still be asymptomatic, but areprogressing toward end-stage chronic renalfailure11. Ix JH et al. Lange Pathophysiology. Lange Medical Books/McGraw Hill, Medical Publishing Division; 2006:456-481;2. Eaton DC et al. Vander's Renal Physiology. Lange Medical Books/McGraw Hill, Medical Publishing Division; 2004:24-36.6

Defining GFRGlomerular filtration– Process by which water and solutes in the blood passfrom the vascular system through a filtration barrierinto Bowman space– This filtrate is similar to blood plasma, with largeplasma proteins excludedGFR– Volume of filtrate formed per unit of time– Normal young adult male: 180 L/d (125 mL/min/1.73m 2)– Entire plasma volume is filtered by kidneys 60 timesper dayEaton DC et al. Vander’s Renal Physiology. Lange Medical Books/McGraw Hill, Medical Publishing Division; 2004:1-23.7

Factors Affecting GFRDirect determinants of GFR– Permeability of capillaries and surface area (filtrationcoefficient)– Net filtration pressure (hydrostatic pressure incapillaries and in Bowman capsule, and glomerularcapillary osmotic pressure resulting from proteins)Other factors that affect GFR– Changes in renal arterial pressure, renal arteriolarresistance (dilation or constriction), and renal plasmaflow– Intratubular pressure—obstruction of tubule orurinary system– Osmotic pressure—increased protein concentrationEaton DC et al. Vander’s Renal Physiology. Lange Medical Books/McGraw Hill, Medical Publishing Division; 2004:24-36.8

JGA

Estimation of GFRInulin clearanceIothalamate scans24 hour urine collectioneGFRCreatinine

GFR versus Serum CreatinineGFR versusSerum CreatinineGFR versus 24 hrCreatinine Clearance9.0Serum Creatinine (mg/dL)8.07.06.05.04.03.02.01.0Creatinine poorreflector of GFR0.0Creatinine Clearance (mL/min/1.73 m2)24020016012080400020 4060 80 100 120 140 160 180Inulin Clearance (mL/min/1.73 m2)Available at: http//medical.dictionary.thefreedictionary.com/. Accessed on March 1, 2005.Johnson R, et al. Comprehensive Clinical Nephrology. 2000. Mosby. St. Louis. 4.15.1–4.15.15.020 4060 80 100 120 140 160 180Inulin Clearance (mL/min/1.73 m2)

GFR Equations ComparedCockcroft-Gault[140 - age] x weight (kg) x (0.85 symbol for female)[72 x PCr]MDRD186.3 x PCr –1.154 x age –0.203 x(0.742(1.212 xiffemale)if black)6 variable: Cr, BUN, age, alb, race, sex4 variable: Cr, age, race, sexLevey AS, et al. Ann Intern Med. 1999;130(6):461-470. Abstract

Pharmacokinetics

PharmacokineticsAbsorption and bioavailabilityDrug distributionVolume of distributionProtein bindingBiotransformation and drug metabolismElimination

BioavailabilityProportion of oral drug reaching systemiccirculationAffected byIntestinal and drug permeabilityFirst pass effectGut motilitypH

Plasma Protein BindingAcidic drugs bind to albumin and basic drugs toα1-acid glycoprotein in the plasmaThere is a decrease in binding of acidic drugs inCKD which has been attributed to changes inthe binding site, accumulation of endogenousinhibitors of binding and decreasedconcentrations of albumin.On the other hand the concentration of α1-acidglycoprotein does not change that much andactually might be increased in patients on HDand transplanted patients

Nephrotic SyndromeComplex interactionHypoalbuminemia may result in lesserprotein binding with more free drug in theplasma while at the same time there mightbe loss of albumin bound drug in the urineSome drugs are also known to produceadverse effects more readily in patientswith nephrotic syndrome eg clofibrate canproduce severe muscle necrosis

Volume of Distribution (VD)Apparent number as it does not correlate with anydefined anatomic spaceIt is a ratio of the administered dose to plasmaconcentration at equilibriumVolume of distribution can vastly exceed any physicalvolume in the body because it is the volume apparentlynecessary to contain the amount of drughomogeneously at the concentration found in the blood,plasma, or water.Concept important for predicting the loading dose

Factors affecting VDProtein and tissue bindingVolume status

Half Life

MetabolismDrug metabolism occurs in the kidneys but to alesser extent than the liverProgressive CKD effects most body biochemicalreactions including drug biotransformationReduction and hydrolysis reactions are slowedbut glucuronidation, sulfation, conjugation andmicrosomal oxidation reactions occur at normalratesAlso important to keep in mind is the fact thateven though the drug might not be eliminated bythe kidney, their active metabolite might egmeperidine, nitrofurantoin and morphine

Dosing in a patient with renalinsufficiency

Extracorporeal Drug Losses

DialysisDialysis is extracorporeal purification ofbloodArtificial Kidney

DialysisDiffusion of small molecules down theirconcentration gradient across asemipermeable membrane

RRTSolute clearanceDiffusionConvectionFluid clearance

Hemo-Dialysis (HD)Concentration difference across a semipermeable membrane favors diffusive transportof small solutes ( 300 Da)

DiffusionUrea is used as the marker for smallmolecule diffusion during dialysisDiffusive clearance is a function ofBlood flow rateMembrane surface areaTime

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Ultra-filtrationRemoval of water during dialysis from thepatients circulationHD – Transmembrane pressure gradientPD – Osmotically driven by glucose

UltrafiltrationUF is a function of three factors1. Transmembrane hydrostatic pressure2. Ultra-filtration coefficient of dialysismembrane3. Duration

Factors Affecting Drug Clearance byDialysisDrugMolecular weightProtein bindingVolume of distribution

Factors Affecting Drug Clearance byDialysisDialysisComposition of the dialyzer membraneSurface areaBlood and dialysate flowMode: IHD, PD or CRRT

HemoperfusionExtracorporeal form of treatment where largevolumes of blood is passed over an adsorbentsurfaceActivated carbon (irreversibly bound by van derWaals’ forces) and resins (not irreversiblybound) are the adsorbents most commonlyused.Higher MW (100-40,000 daltons) are welladsorbed with charcoal having greater affinity forwater soluble and resin for lipid solublecompoundsTime factor

MARSMolecular Adsorbent Recirculating SystemEffectively removes protein bound toxins

Diuresis at controlled pHNonionized drugs are lipid soluble and willdiffuse through cell membranes relativelyeasily, promoting passive absorption offiltered drugs. By contrast, drugs in theionized states are poor absorbed.Alteration in the urine pH can alter theabsorption of weak acids and bases.

Nephrotoxicity

Causes of Acute Renal Failure RBF fromVolume DepletionPrerenal AzotemiaDirect Tubular CellToxicity and NecrosisAcute Tubular NecrosisIntratubularCrystal DepositionCrystal Nephropathy GFRAllergic Reaction inthe InterstitiumAllergic InterstitialNephritisObstruction from StonesPostrenal AzotemiaValeri A, Neusy AJ. Clin Nephrol. 1991;35(3):110-118.Rao TKS, Friedman EA. Am J Kidney Dis. 1995;25(3):390-398.Perazella MA. Am J Med Sci. 2000;319(6):385-391.

TENOFOVIRTenofovir closelyrelated to adefovirAdefovir is a welldescribed nephrotoxinTenofovir freelyfiltered; also secretedby proximal tubuleNephrotoxicityvigilance in uleOAT1MRPLumen

Toxicology

6 GFR as an Indicator of Kidney Function GFR is an important indicator of CKD Reduced GFR in patients with renal disease results from irreversible loss of nephrons 1,2 – Greater burden is placed on remaining nephrons – Hyperfiltration predisposes to further nephron destruction 50